1. Field of the Invention
The present invention relates to a process and system for non-invasively measuring cerebral blood flow by near-infrared spectroscopy and more particularly to near-infrared spectroscopy which uses the intravenous administration of a tracer dye.
2. Description of the Related Art
Near-infrared spectroscopy (NIRS), was described for the first time in 1977 by Jobsis (Jobsis, F. F.: Science 198 (1977), 1264-1267), and represents a relatively new method that makes it possible to non-invasively detect changes in the concentration of chromophores having absorption properties in the near-infrared spectrum in the tissue. The light emitted by a laser at the surface of the body in the near-infrared spectrum (.lambda.=700-1000 nm) can, in contrast to visible light, penetrate endogenous tissue up to a depth of 6 cm. See Van der Zee, P. et al.: Adv. Exp. Med. Biol. 316 (1992), 143-153. In doing so, part of the light is scattered and reflected and can again be detected at the surface of the body by a photomultiplier. Chromophores in the tissue with absorption properties in the range of the emitted light are able, depending on their concentration, to absorb the incident light and thus reduce the amount of light emitted. According to the Beer-Lambert law, the concentration of chromophores in the tissue can be deduced from the light absorption, i.e., the optical density of the tissue.
A noninvasive method for measuring cerebral blood flow by near-infrared spectroscopy (NIRS) was developed in 1988 by Edwards et al. (Edwards, A. D. et al.: The Lancet 2 (1988), 770-771).
The method developed by Edwards et al. uses HbO.sub.2 as a tracer substance for measuring cerebral blood circulation. The concentration of the tracer in the blood is rapidly raised by a sudden increase in the oxygen content of inhaled air (FiO.sub.2). The surge of the "tracer" in the cerebral circulation is detected by NIRS and, based on the Fick principle, is calculated by comparison with the surge of cerebral blood flow detected peripherally by pulsoximetry (Edwards, A. D. et al.: J. Appl. Physiol. 75 (1993), 1884-1889; Elwell, C. E. et al.: Adv. Exp. Med. Biol. 317 (1992), 235-245; Elwell, C. E. et al.: J. Appl. Physiol. 77 (1994), 2753-2760; Elwell, C. E. et al.: Acta Neurosurgery 59 (1993), 74-80). The methodology is validated by comparison with a plethysmographic blood flow measurement at the underarm (Edwards, A. D. et al.: J. Appl. Physiol. 75 (1993), 1884-1889).
One drawback of the method described by Edwards is that the surge of the tracer substance cannot be precisely controlled, since the rapid oxygenation of hemoglobin with the increase in FiO.sub.2 depends on ventilation. Further, the concentration of the tracer substance, even with the most rapid increase in HbO.sub.2, will not increase rapidly enough to achieve optimal determination of the CBF (cerebral blood flow). To achieve a measurable increase in HbO.sub.2 by increasing FiO.sub.2, first a lowering of the HbO.sub.2 by hypoventilation is necessary. However, this generally does not occur in traumatized patients whom a measurement of the CBF would be clinically relevant.
Another drawback of the method described by Edwards et al. is that it is an invasive method. Because it requires the implantation of an additional intravascular, fiber-optic measuring catheter it is not suited for rapid, noninvasive measurement of cerebral blood flow.
For these reasons, Roberts et al. (Roberts, I. et al.: The Lancet 342 (1993), 1425) modified the methodology by using, instead of HbO.sub.2, an intravenously administered dye as the tracer substance. The dye indocyanine green (1-[sulfobutyl]-3,3-dimethyl-2-[7-[-4-sulfobutyl]-3,3-dimethyl-4,5-benzoin dolinylidene-[2]]-heptatriene-[1,3,5]-yl]4,5,benzoindolium) with a molecular weight of 774,97 Daltons (Cherrick, G. R. et al.: J. Clin. Invest. 39 (1960), 592-600), has a maximum absorption rate of about 805 nm and thus lies in the spectrum of near-infrared light (Landsman, M. L. J. et al.: J. Appl. Physiol. 40 (1976), 575-583). After intravenous administration, the dispersion of indocyanine green by the 95% bonding to plasma proteins (Muckle, T. J.: Biochem. Med. 15 (1976), 17-21), especially .alpha.-lipoproteins, is strictly limited to the intravascular compartment (Cherrick, G. R. et al.: J. Clin. Invest. 39 (1960), 592-600). In this way, it is extraordinarily suited as an intravascular tracer. Since it is eliminated quickly by the liver from the circulatory system (Cherrick, G. R. et al.: J. Clin. Invest. 39 (1960), 592-600), repeated measurements at brief intervals are possible. The particular light-absorbing properties of indocyanine green in the near-infrared spectrum make it possible to detect its presence by near-infrared spectroscopy.
Roberts et al. tried to use, instead of the endogenous tracer HbO.sub.2, an intravenous bolus injection of indocyanine green as the tracer substance and again, using the Fick principle, to calculate cerebral blood flow. For this purpose, the surge of indocyanine green in the cerebral vascular system was detected by NIRS and simultaneously the surge of the dye in the arteries was recorded by an invasively implanted arterial catheter. The cerebral blood flow was then determined as CBF=k(Q(t)/(.sub.O.intg..sup.t (Pa)dt)), where CBF is the cerebral blood flow [ml/(100 g.times.min)], k is the constant consisting of the molecular weight of indocyanine green and the density of the cerebral tissue, Q is the accumulation of tracer in the brain measured by NIRS, and P(a) is the arterial concentration of the tracer measured invasively by an intravascular, fiber optic catheter.
In contrast, the device according to the present invention uses two spectroscopes and thus makes it possible to simultaneously measure the relative circulation of blood in the brain through both hemispheres. The near-infrared spectroscope NIRO 500 produced by Hamamatsu Photonics used by Roberts et al. comprises four pulsed lasers in the near-infrared spectrum range, whereas in the present device only two pulsed monochromatic light sources are used for each hemisphere of the brain, one for a measuring wavelength and one for a reference wavelength in the near-infrared spectrum range.
Finally, the arterial dye curve is measured in the device described by Roberts et al. by a fiber optic catheter implanted invasively intra-arterially. The system of the present invention in contrast uses noninvasive measurement of the arterial dye curve by a measuring device using pulse densitometry. The invasiveness of the device and process described by Roberts et al. represents an essential difference compared to the system and process of the present invention, since the implantation of a fiber optic catheter is a surgical procedure having the medical risks of infection, perforation or thrombosis/embolism. In contrast, pulse densitometry is performed non-invasively and thus does not encompass any of the prior art risks described above.
With respect to the measuring procedure, the method used by Roberts et al. clearly differs from the one described herein. In the first place the cerebral blood flow is calculated on the basis of the Fick principle, whereas the process of the present invention is performed by doing a transport function analysis of the indicator dilution curve by deconvolution and subsequently determining a relative blood flow index based on the transcerebral dye transport function. Both processes for measuring cerebral blood flow by near-infrared spectroscopy and intravenous administration of a tracer dye were not validated, i.e., the measurement values obtained were not compared with an independent method. In a briefly conducted study, (Kuebler, W. M. et al.: Int. J. Microcirc.: Clin. Exp. 16 Sl (1996), 223) it was proven for the first time that the measurement values obtained with one of the two methods described above in no way reflects cerebral blood circulation, but rather are the expression of cardiac volume, of which brain blood circulation is independent because of its ability to regulate itself over a wide range.
Proctor et al. (Proctor, H. J. et al.: Surgery 96 (1984), 273-279) used, for the first time in 1984, the intravenous administration of indocyanine green as a tracer substance for determining cerebral blood circulation by near-infrared spectroscopy. They calculated the integral using the surge curve measured by NIRS after intravenous administration of a defined bolus of indocyanine green.
A new process for measuring cerebral blood flow with the aid of a dual indicator dilution method (Mielck, F. et al.: Abstract Book, The European Association of Cardiothoracic Anesthesiologists 11 (1996), 7), makes it possible to quickly and repeatedly determine the CBF of a sickbed patient. Like Edwards, this method is based on an invasive measurement using an intravascular indwelling catheter and offers no breakdown by brain region.
The process disclosed by Hoeft, like Roberts et al., is also based on deconvolution (international AZ PCT/DE95/01690) or Mielck et al., but uses a dual indicator dilution process by determination of a dye kinetic and a thermodilution, and cerebral blood flow in particular is based solely on the thermodilution method (highly diffusible tracer). In contrast, the measurement described in the present invention is based solely on the determination of a dye kinetic (intravascular tracer). The device and measuring process of the Hoeft application differs completely from the present invention especially with regard to the invasiveness of the measurement means which includes surgical implantation of two combined fiber optic-thermistor catheters. Common to both measuring processes is the determination of a transcerebral transport function of the indicator used in each case by calculating a so-called convolution integral by a standardized deconvolution process. The transport functions calculated this way, which contain the characteristic transmission properties of a system, are widespread in natural and engineering sciences as so-called weight functions (Hoeft, A., Dilution Techniques and Fick Principle. In: Monitoring in Anaesthesia and Intensive Medicine, edited by W.F. List, H. Metzler, and T. Pasch, Berlin, Heidelberg, New York: Springer Verlag, 1995 p. 250-291).
Thus, until the present invention, no method has been developed that allows, on an in bed patient, rapid, repeated, noninvasive measurement, broken down by region, of cerebral blood flow (CBF), the adequate regulation of which is an unconditional prerequisite for intact neuronal activity of the brain.